tbuckley/cabot-search huggingface dataset:
An iterative neural processing sequence orchestrates feeding
Authors: Qingqing Liu, Xing Yang, Moxuan Luo, Junying Su, Jinling Zhong, Xiaofen Li, Rosa H.M. Chan, Liping Wang
Journal: Neuron (2023)

Feeding requires sophisticated orchestration of neural processes to satiate appetite in natural, capricious settings. However, the complementary roles of discrete neural populations in orchestrating distinct behaviors and motivations throughout the feeding process are largely unknown. Here, we delineate the behavioral repertoire of mice by developing a machine-learning-assisted behavior tracking system and show that feeding is fragmented and divergent motivations for food consumption or environment exploration compete throughout the feeding process. An iterative activation sequence of agouti-related peptide (AgRP)-expressing neurons in arcuate (ARC) nucleus, GABAergic neurons in the lateral hypothalamus (LH), and in dorsal raphe (DR) orchestrate the preparation, initiation, and maintenance of feeding segments, respectively, via the resolution of motivational conflicts. The iterative neural processing sequence underlying the competition of divergent motivations further suggests a general rule for optimizing goal-directed behaviors.
Subcellular mRNA localization and local translation of Arhgap11a in radial glial progenitors regulates cortical development
Authors: Louis-Jan Pilaz, Jing Liu, Kaumudi Joshi, Yuji Tsunekawa, Camila M. Musso, Brooke R. D’Arcy, Ikuo K. Suzuki, Fernando C. Alsina, Pratiksha KC, Sahil Sethi, Pierre Vanderhaeghen, Franck Polleux, Debra L. Silver
Journal: Neuron (2023)
Comparative effectiveness of BNT162b2 versus mRNA-1273 covid-19 vaccine boosting in England: matched cohort study in OpenSAFELY-TPP
Authors: William J Hulme, Elsie M F Horne, Edward P K Parker, Ruth H Keogh, Elizabeth J Williamson, Venexia Walker, Tom M Palmer, Helen J Curtis, Alex J Walker, Colm D Andrews, Amir Mehrkar, Jessica Morley, Brian MacKenna, Sebastian C J Bacon, Ben Goldacre, Miguel A Hernán, Jonathan A C Sterne
Journal: BMJ (2023)

Abstract Objective To compare the effectiveness of the BNT162b2 mRNA (Pfizer-BioNTech) and mRNA-1273 (Moderna) covid-19 vaccines during the booster programme in England. Design Matched cohort study, emulating a comparative effectiveness trial. Setting Linked primary care, hospital, and covid-19 surveillance records available within the OpenSAFELY-TPP research platform, covering a period when the SARS-CoV-2 delta and omicron variants were dominant. Participants 3 237 918 adults who received a booster dose of either vaccine between 29 October 2021 and 25 February 2022 as part of the national booster programme in England and who received a primary course of BNT162b2 or ChAdOx1. Intervention Vaccination with either BNT162b2 or mRNA-1273 as a booster vaccine dose. Main outcome measures Recorded SARS-CoV-2 positive test, covid-19 related hospital admission, covid-19 related death, and non-covid-19 related death at 20 weeks after receipt of the booster dose. Results 1 618 959 people were matched in each vaccine group, contributing a total 64 546 391 person weeks of follow-up. The 20 week risks per 1000 for a positive SARS-CoV-2 test were 164.2 (95% confidence interval 163.3 to 165.1) for BNT162b2 and 159.9 (159.0 to 160.8) for mRNA-1273; the hazard ratio comparing mRNA-1273 with BNT162b2 was 0.95 (95% confidence interval 0.95 to 0.96). The 20 week risks per 1000 for hospital admission with covid-19 were 0.75 (0.71 to 0.79) for BNT162b2 and 0.65 (0.61 to 0.69) for mRNA-1273; the hazard ratio was 0.89 (0.82 to 0.95). Covid-19 related deaths were rare: the 20 week risks per 1000 were 0.028 (0.021 to 0.037) for BNT162b2 and 0.024 (0.018 to 0.033) for mRNA-1273; hazard ratio 0.83 (0.58 to 1.19). Comparative effectiveness was generally similar within subgroups defined by the primary course vaccine brand, age, previous SARS-CoV-2 infection, and clinical vulnerability. Relative benefit was similar when vaccines were compared separately in the delta and omicron variant eras. Conclusions This matched observational study of adults estimated a modest benefit of booster vaccination with mRNA-1273 compared with BNT162b2 in preventing positive SARS-CoV-2 tests and hospital admission with covid-19 20 weeks after vaccination, during a period of delta followed by omicron variant dominance.
Exosome/metformin-loaded self-healing conductive hydrogel rescues microvascular dysfunction and promotes chronic diabetic wound healing by inhibiting mitochondrial fission
Authors: Yue Zhang, Meng Li, Yunchuan Wang, Fei Han, Kuo Shen, Liang Luo, Yan Li, Yanhui Jia, Jian Zhang, Weixia Cai, Kejia Wang, Ming Zhao, Jing Wang, Xiaowen Gao, Chenyang Tian, Baolin Guo, Dahai Hu
Journal: Bioactive Materials (2023)

Chronic diabetic wounds remain a globally recognized clinical challenge. They occur due to high concentrations of reactive oxygen species and vascular function disorders. A promising strategy for diabetic wound healing is the delivery of exosomes, comprising bioactive dressings. Metformin activates the vascular endothelial growth factor pathway, thereby improving angiogenesis in hyperglycemic states. However, multifunctional hydrogels loaded with drugs and bioactive substances synergistically promote wound repair has been rarely reported, and the mechanism of their combinatorial effect of exosome and metformin in wound healing remains unclear. Here, we engineered dual-loaded hydrogels possessing tissue adhesive, antioxidant, self-healing and electrical conductivity properties, wherein 4-armed SH-PEG cross-links with Ag+, which minimizes damage to the loaded goods and investigated their mechanism of promotion effect for wound repair. Multiwalled carbon nanotubes exhibiting good conductivity were also incorporated into the hydrogels to generate hydrogen bonds with the thiol group, creating a stable three-dimensional structure for exosome and metformin loading. The diabetic wound model of the present study suggests that the PEG/Ag/CNT-M + E hydrogel promotes wound healing by triggering cell proliferation and angiogenesis and relieving peritraumatic inflammation and vascular injury. The mechanism of the dual-loaded hydrogel involves reducing the level of reactive oxygen species by interfering with mitochondrial fission, thereby protecting F-actin homeostasis and alleviating microvascular dysfunction. Hence, we propose a drug-bioactive substance combination therapy and provide a potential mechanism for developing vascular function-associated strategies for treating chronic diabetic wounds.
Bold action is needed to strengthen primary prevention
Authors: Petra Meier, Srinivasa Vittal Katikireddi, Katherine Smith
Journal: BMJ (2023)

Primary prevention tackles the underlying causes of ill health, preventing or substantially delaying onset, reducing the burden of disease in populations, and helping individuals live longer, healthier lives.In turn, this reduces pressure on health and social care systems.Primary prevention promotes health equity by addressing the unequal distribution of the social, economic, environmental, and commercial determinants of health-for example, through reducing poverty, regulating air quality, or taxing unhealthy commodities. 1 It also makes economic sense: it is often more cost effective to prevent disease than to treat it,
Engineered macrophage-biomimetic versatile nanoantidotes for inflammation-targeted therapy against Alzheimer's disease by neurotoxin neutralization and immune recognition suppression
Authors: Meng Cheng, Caihua Ye, Chunxiao Tian, Dongju Zhao, Haonan Li, Zuhao Sun, Yuyang Miao, Qiang Zhang, Junping Wang, Yan Dou
Journal: Bioactive Materials (2023)

Immune recognition of excessive neurotoxins by microglia is a trigger for the onset of neuroinflammation in the brain, leading to neurodegeneration in Alzheimer's disease (AD). Blocking active recognition of microglia while removing neurotoxins holds promise for fundamentally alleviating neurotoxin-induced immune responses, but is very challenging. Herein, an engineered macrophage-biomimetic versatile nanoantidote (OT-Lipo@M) is developed for inflammation-targeted therapy against AD by neurotoxin neutralization and immune recognition suppression. Coating macrophage membranes can not only endow OT-Lipo@M with anti-phagocytic and inflammation-tropism capabilities to target inflammatory lesions in AD brain, but also efficiently reduce neurotoxin levels to prevent them from activating microglia. The loaded oxytocin (OT) can be slowly released to downregulate the expression of immune recognition site Toll-like receptor 4 (TLR4) on microglia, inhibiting TLR4-mediated pro-inflammatory signalling cascade. Benefiting from this two-pronged immunosuppressive strategy, OT-Lipo@M exhibits outstanding therapeutic effects on ameliorating cognitive deficits, inhibiting neuronal apoptosis, and enhancing synaptic plasticity in AD mice, accompanied by the delayed hippocampal atrophy and brain microstructural disruption by in vivo 9.4T MR imaging. This work provides new insights into potential AD therapeutics targeting microglia-mediated neuroinflammation at the source.
Cognitive impairment after cancer treatment: mechanisms, clinical characterization, and management
Authors: Ben Fleming, Paul Edison, Laura Kenny
Journal: BMJ (2023)

Abstract Cognitive impairment is a debilitating side effect experienced by patients with cancer treated with systemically administered anticancer therapies. With around 19.3 million new cases of cancer worldwide in 2020 and the five year survival rate growing from 50% in 1970 to 67% in 2013, an urgent need exists to understand enduring side effects with severe implications for quality of life. Whereas cognitive impairment associated with chemotherapy is recognized in patients with breast cancer, researchers have started to identify cognitive impairment associated with other treatments such as immune, endocrine, and targeted therapies only recently. The underlying mechanisms are diverse and therapy specific, so further evaluation is needed to develop effective therapeutic interventions. Drug and non-drug management strategies are emerging that target mechanistic pathways or the cognitive deficits themselves, but they need to be rigorously evaluated. Clinically, consistent use of objective diagnostic tools is necessary for accurate diagnosis and clinical characterization of cognitive impairment in patients treated with anticancer therapies. This should be supplemented with clinical guidelines that could be implemented in daily practice. This review summarizes the recent advances in the mechanisms, clinical characterization, and novel management strategies of cognitive impairment associated with treatment of non-central nervous system cancers.
Corrigendum to “Epigallocatechin-3-gallate/mineralization precursors co-delivery hollow mesoporous nanosystem for synergistic manipulation of dentin exposure” [Bioact. Mater. 23 (2023) 394–408]
Authors: Jian Yu, Haolin Bian, Yaning Zhao, Jingmei Guo, Chenmin Yao, He Liu, Ya Shen, Hongye Yang, Cui Huang
Journal: Bioactive Materials (2023)

[This corrects the article DOI: 10.1016/j.bioactmat.2022.11.018.].
Bilirubin gates the TRPM2 channel as a direct agonist to exacerbate ischemic brain damage
Authors: Han-Wei Liu, Li-Na Gong, Ke Lai, Xia-Fei Yu, Zhen-Qi Liu, Ming-Xian Li, Xin-Lu Yin, Min Liang, Hao-Song Shi, Lin-Hua Jiang, Wei Yang, Hai-Bo Shi, Lu-Yang Wang, Shan-Kai Yin
Journal: Neuron (2023)

Stroke prognosis is negatively associated with an elevation of serum bilirubin, but how bilirubin worsens outcomes remains mysterious. We report that post-, but not pre-, stroke bilirubin levels among inpatients scale with infarct volume. In mouse models, bilirubin increases neuronal excitability and ischemic infarct, whereas ischemic insults induce the release of endogenous bilirubin, all of which are attenuated by knockout of the TRPM2 channel or its antagonist A23. Independent of canonical TRPM2 intracellular agonists, bilirubin and its metabolic derivatives gate the channel opening, whereas A23 antagonizes it by binding to the same cavity. Knocking in a loss of binding point mutation for bilirubin, TRPM2-D1066A, effectively antagonizes ischemic neurotoxicity in mice. These findings suggest a vicious cycle of stroke injury in which initial ischemic insults trigger the release of endogenous bilirubin from injured cells, which potentially acts as a volume neurotransmitter to activate TRPM2 channels, aggravating Ca2+-dependent brain injury.
The rapid rise of SARS‐CoV‐2 Omicron subvariants with immune evasion properties: XBB.1.5 and BQ.1.1 subvariants
Authors: Danyi Ao, Xuemei He, Weiqi Hong, Xiawei Wei
Journal: MedComm (2023)

As the fifth variant of concern of the SARS-CoV-2 virus, the Omicron variant (B.1.1.529) has quickly become the dominant type among the previous circulating variants worldwide. During the Omicron wave, several subvariants have emerged, with some exhibiting greater infectivity and immune evasion, accounting for their fast spread across many countries. Recently, two Omicron subvariants, BQ.1 and XBB lineages, including BQ.1.1, XBB.1, and XBB.1.5, have become a global public health issue given their ability to escape from therapeutic monoclonal antibodies and herd immunity induced by prior coronavirus disease 2019 (COVID-19) vaccines, boosters, and infection. In this respect, XBB.1.5, which has been established to harbor a rare mutation F486P, demonstrates superior transmissibility and immune escape ability compared to other subvariants and has emerged as the dominant strain in several countries. This review provides a comprehensive overview of the epidemiological features, spike mutations, and immune evasion of BQ.1 and XBB lineages. We expounded on the mechanisms underlying mutations and immune escape from neutralizing antibodies from vaccinated or convalescent COVID-19 individuals and therapeutic monoclonal antibodies (mAbs) and proposed strategies for prevention against BQ.1 and XBB sublineages.
Corynoxine B targets at HMGB1/2 to enhance autophagy for α-synuclein clearance in fly and rodent models of Parkinson's disease
Authors: Qi Zhu, Juxian Song, Jia-Yue Chen, Zhenwei Yuan, Liangfeng Liu, Li-Ming Xie, Qiwen Liao, Richard D. Ye, Xiu Chen, Yepiao Yan, Jieqiong Tan, Chris Soon Heng Tan, Min Li, Jia-Hong Lu
Journal: Acta Pharmaceutica Sinica B (2023)

Parkinson's disease (PD) is the most common neurodegenerative movement disease. It is featured by abnormal alpha-synuclein (α-syn) aggregation in dopaminergic neurons in the substantia nigra. Macroautophagy (autophagy) is an evolutionarily conserved cellular process for degradation of cellular contents, including protein aggregates, to maintain cellular homeostasis. Corynoxine B (Cory B), a natural alkaloid isolated from Uncaria rhynchophylla (Miq.) Jacks., has been reported to promote the clearance of α-syn in cell models by inducing autophagy. However, the molecular mechanism by which Cory B induces autophagy is not known, and the α-syn-lowering activity of Cory B has not been verified in animal models. Here, we report that Cory B enhanced the activity of Beclin 1/VPS34 complex and increased autophagy by promoting the interaction between Beclin 1 and HMGB1/2. Depletion of HMGB1/2 impaired Cory B-induced autophagy. We showed for the first time that, similar to HMGB1, HMGB2 is also required for autophagy and depletion of HMGB2 decreased autophagy levels and phosphatidylinositol 3-kinase III activity both under basal and stimulated conditions. By applying cellular thermal shift assay, surface plasmon resonance, and molecular docking, we confirmed that Cory B directly binds to HMGB1/2 near the C106 site. Furthermore, in vivo studies with a wild-type α-syn transgenic drosophila model of PD and an A53T α-syn transgenic mouse model of PD, Cory B enhanced autophagy, promoted α-syn clearance and improved behavioral abnormalities. Taken together, the results of this study reveal that Cory B enhances phosphatidylinositol 3-kinase III activity/autophagy by binding to HMGB1/2 and that this enhancement is neuroprotective against PD.
Over-interpretation of findings in diagnostic accuracy studies of infectious diseases
Authors: Solange Bramer, Ho Yee Cheung, Wesley Do, Mariska M.G. Leeflang
Journal: Clinical Microbiology and Infection (2023)

To assess the prevalence of overly positive interpretation, also called 'spin',-of results in diagnostic accuracy studies of infectious diseases and to identify suggestions for improvement.A PubMed search was performed to identify diagnostic accuracy studies of infectious diseases published between January and March 2019. Each article was assessed by two authors independently to identify study characteristics and forms of actual and potential over-interpretation. 'Actual over-interpretation' was defined as conclusions that were not on the basis of study aims or conclusions that were more favourable than justified by the study findings. There are other practices that may result in the over-interpretation of study findings and these have been described as 'potential over-interpretation'.The final analysis included 120 studies. Favourable or promising recommendations were made in the main text of 101 (84%) of the included studies. Evidence of actual over-interpretation (spin) was found in 30 (25%) articles, with 22 (18%) studies reporting a conclusion that did not match the study aims and 56 (47%) studies with a more positive conclusion in the abstract than the main text. All analysed studies exhibited at least one form of potential over-interpretation, with was most commonly a lack of sample size calculation (n = 109, 91%) and not reporting a null hypothesis (n = 115, 96%).Evidence of over-interpretation of results was found in one-third of the included studies. We have proposed possible interventions to prevent overly positive interpretations of results in diagnostic accuracy studies.
The ongoing Streptococcus pyogenes (Group A Streptococcus) outbreak in London, United Kingdom, in December 2022: a molecular epidemiology study
Authors: Adela Alcolea-Medina, Luke B. Snell, Christopher Alder, Themoula Charalampous, Tom G.S. Williams, Mark K.I. Tan, Noor Al-Yaakoubi, Gul Humayun, William Newsholme, Simon Goldenberg, Gaia Nebbia, Stuart J.D. Neil, Rahul Batra, Jonathan D. Edgeworth, Vasanthini Athitha, Jahaedea Begum, Massimo Bonaiti, Julie Brennan, Lisa Bryan, Albert Cerda, Penelope R. Cliff, Luong Huw Hoang, Tammy V. Merrill, Denitsa Naumova, Rayhan Parvez, Kristine Valle, Sarah White, Diane Wray
Journal: Clinical Microbiology and Infection (2023)

Epidemiological and whole-genome sequencing analysis of an ongoing outbreak of Streptococcus pyogenes (Group A Streptococcus) in London (United Kingdom).
Treatment recommendations for acne-associated hyperpigmentation: Results of the Delphi consensus process and a literature review
Authors: Susan Taylor, Nada Elbuluk, Pearl Grimes, Anna Chien, Iltefat Hamzavi, Andrew Alexis, Noelani Gonzalez, Jonathan Weiss, Sewon Kang, Seemal R. Desai
Journal: Journal of the American Academy of Dermatology (2023)
The CCR6/CCL20 axis expands RORγt+ Tregs to protect from glomerulonephritis
Authors: Georg R. Herrnstadt, Christoph B. Niehus, Torben Ramcke, Julia Hagenstein, Laura-Isabell Ehnold, Anna Nosko, Matthias T. Warkotsch, Frederic C. Feindt, Simon Melderis, Hans-Joachim Paust, Varshi Sivayoganathan, Saskia-Larissa Jauch-Speer, Milagros N. Wong, Daniela Indenbirken, Christian F. Krebs, Tobias B. Huber, Ulf Panzer, Victor G. Puelles, Malte A. Kluger, Oliver M. Steinmetz
Journal: Kidney International (2023)
Genetic variant in complement receptor 1 (CR1, CD35) is associated with a cluster of severe fatal COVID-19 in a family
Authors: N. Danial-Farran, M. Khlaila, M. Avraham-Kelbert, B. Chazan, M. Khayat, A. Winder, S. Shalev, N. Bisharat
Journal: Journal of Infection (2023)
Open-Globe Injury Repairs in the American Academy of Ophthalmology IRIS® Registry 2014 – 2018
Authors: Maurizio Tomaiuolo, Fasika A. Woreta, Alexander Li, Yoshihiro Yonekawa, Qiang (Ed) Zhang, James E. Sharpe, Sidra Zafar, Zeba A. Syed, Sathyadeepak Ramesh, Alice C. Lorch, Nathan E. Hall, Ankoor S. Shah, Grant A. Justin, Leslie Hyman, Aaron Y. Lee, Cecilia S. Lee, Russ Van Gelder, Alice Lorch, Joan W. Miller, Suzann Pershing, Jeffrey Goldberg
Journal: Ophthalmology (2023)
Delayed diagnosis resulting in increased disease burden in multiple myeloma: the legacy of the COVID-19 pandemic
Authors: Jonathan Carmichael, Frances Seymour, Graham McIlroy, Sarrah Tayabali, Rosie Amerikanou, Sylvia Feyler, Rakesh Popat, Guy Pratt, Christopher Parrish, A. John Ashcroft, Graham H. Jackson, Gordon Cook
Journal: Blood Cancer Journal (2023)

The COVID-19 pandemic has had global healthcare impacts, including high mortality from SARS-CoV-2 infection in cancer patients; individuals with multiple myeloma (MM) are especially susceptible to poor outcomes. However, even for MM patients who avoided severe infection, the ramifications of the pandemic have been considerable. The consequences of necessary socio-geographical behavior adaptation, including prolonged shielding and interruptions in delivery of non-pandemic medical services are yet to be fully understood. Using a real-world dataset of 323 consecutive newly diagnosed MM patients in England, we investigated the impact of the COVID-19 pandemic on routes to myeloma diagnosis, disease stage at presentation and relevant clinical outcomes. We demonstrate increasing MM presentations via emergency services and increased rates of bony and extra-medullary disease. Differences were seen in choice of induction therapy and the proportion of eligible patients undertaking autologous stem cell transplantation. Whilst survival was statistically inferior for emergency presentations, significant survival differences have yet to be demonstrated for the entire cohort diagnosed during the pandemic, making extended follow-up critical in this group. This dataset highlights wide-ranging issues facing MM patients consequent of the COVID-19 pandemic, with full impacts for clinicians and policy-makers yet to be elucidated.
MALT1-dependent cleavage of CYLD promotes NF-κB signaling and growth of aggressive B-cell receptor-dependent lymphomas
Authors: Marthe Minderman, Hildo C. Lantermans, Leonie J. Grüneberg, Saskia A. G. M. Cillessen, Richard J. Bende, Carel J. M. van Noesel, Marie José Kersten, Steven T. Pals, Marcel Spaargaren
Journal: Blood Cancer Journal (2023)

Abstract The paracaspase mucosa-associated lymphoid tissue 1 (MALT1) is a protease and scaffold protein essential in propagating B-cell receptor (BCR) signaling to NF-κB. The deubiquitinating enzyme cylindromatosis (CYLD) is a recently discovered MALT1 target that can negatively regulate NF-κB activation. Here, we show that low expression of CYLD is associated with inferior prognosis of diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) patients, and that chronic BCR signaling propagates MALT1-mediated cleavage and, consequently, inactivation and rapid proteasomal degradation of CYLD. Ectopic overexpression of WT CYLD or a MALT1-cleavage resistant mutant of CYLD reduced phosphorylation of IκBα, repressed transcription of canonical NF-κB target genes and impaired growth of BCR-dependent lymphoma cell lines. Furthermore, silencing of CYLD expression rendered BCR-dependent lymphoma cell lines less sensitive to inhibition of NF-κΒ signaling and cell proliferation by BCR pathway inhibitors, e.g., the BTK inhibitor ibrutinib, indicating that these effects are partially mediated by CYLD. Taken together, our findings identify an important role for MALT1-mediated CYLD cleavage in BCR signaling, NF-κB activation and cell proliferation, which provides novel insights into the underlying molecular mechanisms and clinical potential of inhibitors of MALT1 and ubiquitination enzymes as promising therapeutics for DLBCL, MCL and potentially other B-cell malignancies.